Acquired neuropathology and its associations with key patterns of placental pathology

Abstract

Perinatal brain injury is a major cause of neurodevelopmental disability worldwide. Placental pathology has been implicated as a likely cause of injury to the developing central nervous system (CNS). This study aims to elucidate the associations of multiple placental pathologies and CNS injury, including more subtle brain pathologies associated with adverse neurologic outcomes. Sixty-five subjects that underwent complete post-mortem neuropathologic examination and placental examination were selected for inclusion. Gross images, autopsy reports, and histologic sections from the CNS and placenta underwent blinded reviewed by experts in perinatal neuropathology and placental pathology, respectively. Immunostains useful in highlighting CNS lesions not apparent on routine histologic sections were performed. Placental pathology was classified according to the Amsterdam criteria, and all placental and CNS abnormalities were documented. A previously undescribed association between white matter injury and fetal vascular malperfusion was seen, likely due to improved detection of injury on immunohistochemical stains. Amniotic fluid infection was associated with acute neuronal injury in the cortex and cerebellum as well as subarachnoid hemorrhage. Hippocampal injury had the strongest association with high-grade chronic inflammation, and maternal vascular malperfusion showed higher relative frequencies of acute neuronal injury in the basal ganglia, brainstem, and spinal cord. To our knowledge, this is the first study to standardize placental pathology according to the Amsterdam consensus criteria, separate out injury across multiple CNS regions with independent assessment of these regions, and to utilize immunohistochemistry to improve detection of white matter injury. Different patterns of placental pathology were associated with different types of CNS injury, indicating neuronal injury and white matter injury may be influenced by distinct placental pathologies. Elucidating the placental contributions to these acquired CNS pathologies in stillborns is crucial for understanding long-term adverse neurodevelopmental outcomes associated with perinatal brain injury.

Keywords: Amsterdam criteria; Brain; Central nervous system; Injury; Neuropathology; Perinatal; Placenta; Stillbirth.

Fig. 1

Examples and rates of acquired neuropathologies. (A) Acute neuronal injury (apoptosis, marked by arrows) in the pons (H&E, 400x magnification). (B) Diffuse white matter gliosis and a white matter calcification (arrow) (H&E, 200x magnification). (C) Same case as (B) with gliosis better appreciated on GFAP stain (200x magnification). (D) A region of white matter necrosis (APP immunostain, 40x magnification). (E) Rates of acquired CNS pathologies grouped by injury type. (F) Immunohistochemical stains improve the rate of detection of white matter injury. When white matter injury was present, the percentage of subjects requiring IHC for diagnosis is shown in light blue. CPH: choroid plexus hemorrhage; DWMG: diffuse white matter gliosis; GMH: germinal matrix hemorrhage; IHC: immunohistochemistry; IVH: intraventricular hemorrhage; LSV: lenticulostriate vasculopathy; SAH: subarachnoid hemorrhage; SDH: subdural hemorrhage; WMN: white matter necrosis

Fig. 2

Examples and rates of placental pathologies. (A) Example of acute inflammation: acute umbilical phlebitis and funisitis (H&E, 40x magnification). (B) Example of chronic inflammation: chronic villitis with associated avascular villi (H&E, 100x magnification). (C) Example of fetal vascular malperfusion: two stem villous vessels with intramural fibrin deposition/thrombi (H&E, 40x magnification). (D) Example of maternal vascular malperfusion: parabasal remote villous infarction (H&E, 20x magnification). (E) Rates of placental pathologies. AFI: amniotic fluid infection; AVM: Accelerated villous maturation; CI: chronic inflammation; CV: chronic villitis; DVM: delayed villous maturation; FTV: fetal thrombotic vasculopathy; FVM: fetal vascular malperfusion; MPVFD: massive perivillous fibrin deposition; MVM: maternal vascular malperfusion

Fig. 3

Differences in relative frequencies of neuropathologies by presence/absence of placental pathologies. Acquired neuropathologies in the gray and white matter and hemorrhages are shown. Individual values represent the relative frequency of CNS injury when a placental pathology was present minus the frequency of CNS injury in cases lacking that same placental pathology. Values are color coded to represent higher rates of neuropathology in red and lower rates in blue. A color key is shown at the bottom of the figure. Statistically significant values and those approaching significance are highlighted in bold font. Statistical significance is indicated as follows: * = p < 0.05, ** = p < 0.01, § approaching statistical significance, p < 0.0675. N indicates the number of cases in each group. AFI: amniotic fluid infection; AVM: Accelerated villous maturation; CI: chronic inflammation; CV: chronic villitis; DVM: delayed villous maturation; DWMG: diffuse white matter gliosis; FTV: fetal thrombotic vasculopathy; FVM: fetal vascular malperfusion; MPVFD: massive perivillous fibrin deposition; MVM: maternal vascular malperfusion; WMN: white matter necrosis

Fig. 4

Types of CNS injury associated with the four major categories of placental pathology. Shading indicates regions in which high relative frequencies (positive associations) of acute neuronal injury (red) and white matter injury (violet) were seen